The clinical studies in this application are focused on the pathophysiology of type 2 diabetes mellitus and specifically the alterations in islet B-cell function that characterize this disease process. Three specific objectives (with their experimental approaches) have been identified. 1. To determine whether subjects at high risk of developing type 2 diabetes (women with a history of gestational diabetes, individuals with a first degree relative with the disease and individuals with impaired glucose tolerance) have defects in B-cell function that can be exacerbated by increased secretory demand resulting in the development of hyperglycemia. Increased B-cell secretory demand will be produced by inducing experimental insulin resistance with nicotinic acid. 2. To determine whether the disproportionate pro-insulinemia observed in subjects with type 2 diabetes is due to a fundamental alteration in pro- insulin processing or whether it results from an increase in secretory demand with the premature release of B-cell secretory granules. Individuals with type 2 diabetes and healthy controls will be studied before and following 24 hours of islet B-cell result produced by an infusion of somatostatin. 3. To determine whether the disproportionate pro-insulinemia observed in subjects with type 2 diabetes is associated with disproportionate release of pro-islet amyloid polypeptide (proIAPP). An assay for proIAPP will be developed and measurements will be made in plasma from health subjects and subjects with type 2 diabetes to determine whether disproportionate release of proIAPP occurs in type 2 diabetes. The applicant has successfully trained a number of young investigators in the areas of patient-oriented and basic research and a plan to continue doing so is presented.